The goal of the proposed study is to integrate experimental and modeling approaches for the design and implementation of polymeric, nonviral, gene delivery systems. Nonviral gene delivery systems that are efficient and targeted are needed to improve cell modifications and to avoid complications experienced with current nonviral and viral gene delivery systems. It is hypothesized that by using an integrated experimental- computational- approach, a new strategy to guide the preparation and assessment of efficient gene delivery systems can be achieved. Such success would transform the field with a more comprehensive and efficient process. Genetically designed tetra-block protein polymers based on spider silk systems will be used to provide specific control of particle size, binding kinetics, and cell targeting. Integrated multiscale modeling and bioengineering approaches will be used to guide and accelerate the design process. The unique feature of this approach is the highly tailored features controlled via genetic blueprints and the integration of computational predictions to provide iterative feedback to refine the experimental designs (and thus the efficacy) of gene delivery. The plans will be addressed in two iterative Aims, (1) In vitr preparation and characterization of spider silk gene delivery systems and (2) In silico multiscale modeling. The outcome of the proposed work will be experimental data sets that correlate material features with functional outcomes (specificity, transfection efficiency, release kinetics) as predicted by multiscale modeling. We anticipate that the insights from the planned study would provide useful multiscale models that capture the complexity of biomaterials used in gene delivery.